Cyclic stretch of embryonic cardiomyocytes increases proliferation, growth, and expression while repressing Tgf-β signaling

Indroneal Banerjee, Katrina Carrion, Ricardo Serrano, Jeffrey Dyo, Roman Sasik, Sean Lund, Erik Willems, Seema Aceves, Rudolph Meili, Mark Mercola, Ju Chen, Alexander Zambon, Gary Hardiman, Taylor A. Doherty, Stephan Lange, Juan C. del Álamo, Vishal Nigam*

*Corresponding author for this work

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Perturbed biomechanical stimuli are thought to be critical for the pathogenesis of a number of congenital heart defects, including Hypoplastic Left Heart Syndrome (HLHS). While embryonic cardiomyocytes experience biomechanical stretch every heart beat, their molecular responses to biomechanical stimuli during heart development are poorly understood. We hypothesized that biomechanical stimuli activate specific signaling pathways that impact proliferation, gene expression and myocyte contraction. The objective of this study was to expose embryonic mouse cardiomyocytes (EMCM) to cyclic stretch and examine key molecular and phenotypic responses. Analysis of RNA-Sequencing data demonstrated that gene ontology groups associated with myofibril and cardiac development were significantly modulated. Stretch increased EMCM proliferation, size, cardiac gene expression, and myofibril protein levels. Stretch also repressed several components belonging to the Transforming Growth Factor-β (Tgf-β) signaling pathway. EMCMs undergoing cyclic stretch had decreased Tgf-β expression, protein levels, and signaling. Furthermore, treatment of EMCMs with a Tgf-β inhibitor resulted in increased EMCM size. Functionally, Tgf-β signaling repressed EMCM proliferation and contractile function, as assayed via dynamic monolayer force microscopy (DMFM). Taken together, these data support the hypothesis that biomechanical stimuli play a vital role in normal cardiac development and for cardiac pathology, including HLHS.

Original languageEnglish
Pages (from-to)133-144
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume79
DOIs
Publication statusPublished - 01 Feb 2015
Externally publishedYes

Keywords

  • Cardiac development
  • Cardiomyocytes
  • Cell biology/structural biology
  • Contractile function
  • Contractility
  • Gene regulation
  • Hypoplastic Left Heart Syndrome
  • Mechanical stretch
  • Other myocardial biology
  • Pediatric and congenital heart disease
  • Physiologic and pathologic control of gene expression
  • Subject Codes

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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